Duchenne Muscular Dystrophy (DMD) is an inherited disorder caused by mutations in the dystrophin gene. For many years gene therapy has been considered a potential way to cure inherited diseases such as DMD. Despite the effort to make gene therapy safer and more applicable, the host immune response to the vector and the therapeutic gene product is still considered a major barrier to successful gene transfer. We hypothesize that manipulating the immune system of dystrophic mice to recognize dystrophin as a self- component before gene transfer will lead to successful delivery and long-term expression of dystrophin in muscles of these mice. We propose to expand Tregs in the presence of dystrophin protein and to adoptively transfer them into vector-recipient mice to induce dystrophin-specific tolerance in these mice. Results will be obtained from parallel studies to investigate the difference between treating dystrophic mice with high- capacity adenoviral (HC-Ad) and adeno-associated viral (AAV) vectors. These studies will enhance our understanding of effects of inducing antigen-specific tolerance on gene delivery and will ultimately facilitate successful delivery of the dystrophin gene to DMD patients.